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Current Status and Benefits of Therapy for Chronic Hepatitis C Virus (HCV)

Current Status and Benefits of Therapy for Chronic Hepatitis C Virus (HCV). Fuad AM Hasan Department Of Medicine Faculty of Medicine Kuwait University. Current Status and Benefits of Therapy for Chronic Hepatitis C Virus (HCV). Fuad AM Hasan Department Of Medicine Faculty of Medicine

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Current Status and Benefits of Therapy for Chronic Hepatitis C Virus (HCV)

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  1. Current Status and Benefits of Therapy for Chronic Hepatitis C Virus (HCV) Fuad AM Hasan Department Of Medicine Faculty of Medicine Kuwait University

  2. Current Status and Benefits of Therapy for Chronic Hepatitis C Virus (HCV) Fuad AM Hasan Department Of Medicine Faculty of Medicine Kuwait University

  3. Current And Future Treatment of HCV:The Count Down To The Demise of Hepatology Fuad AM Hasan Department Of Medicine Faculty of Medicine Kuwait University

  4. True or False • Hepatitis C is incurable. Treatment only suppresses the virus • Interferon and ribavirin therapy are associated with minor adverse events • HCV genotype is a major determinant of response to interferon based therapy. • Boceprevir and telaprevir are effective against all genotypes. • Sofosbuvir in combination with IFN and ribavirin cures around 90% of HCV infected patients

  5. Outline • HCV structure and life cycle • HCV genotypes • Standard treatment of HCV (2001-2011) • Standard treatment of HCV genotype 1 (2011-2013) • Current treatment of HCV genotypes 1-6 • The future

  6. HCV Polyprotein Processing and Viral Protein Function McGovern B, Abu Dayyeh B, and Chung RT. Hepatology. 2008; 48:1700-12

  7. HCV Life Cycle and DAA Targets Receptor bindingand endocytosis Transportand release Fusion and uncoating LD LD Translation andpolyprotein processing ER lumen Virionassembly (+) RNA LD NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside Membranousweb RNA replication ER lumen NS5A inhibitors Block replication complex formation, assembly RNA replication Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

  8. HCV Genotypes

  9. The Prevalence of HCV Genotype 4 in Kuwait Hasan et al. Hepatogastroenterology2002 * Eastern province of Syria

  10. Seroprevalence of HCV in Kuwait Ameen R et al. Transfusion. 2005 ;45:1973-80. Chehada W et al. J infect Public Health 2011 ;4:200-6 *Al Khalidi J et al. Unpublished data

  11. Treatment of HCV 2001-2011 Pegylated Interferon plus Ribavirin combination was the standard treatment of HCV regardless of genotype until 2011

  12. Sustained Virologic Responses By Genotype *Hasan F, et al. Am J Gastroenterol 2004;99:1733-1737

  13. Interferon Plus Ribavirin TherapyLimitations 20-60 % do not respond Numerous side effects

  14. Factors That Influence Response to Interferon Based Therapy Treatment regimen PEG-IFN Ribavirin DAA Host factors Age, gender, race obesity, co-morbidities Genetic factors (IL28B and ITPA) Factors that affect outcome Disease features Fibrosis, steatosis, co-infection (HBV, HIV) Viral factors Genotype / Subtype Quasispecies / Resistance Viral load

  15. Most Important Factors that Influence Treatment Outcome HCV Genotype IL 28 B Polymorphism Degree of Fibrosis HCV RNA level

  16. Side Effects of PegIFN/Ribavirin Fever Myalgias Hair loss Depression Anemia Rash “Interferon Man” Many others !

  17. Was it the Interferon Man ?

  18. Contraindications of Pegylated Interferon and Ribavirin • De-compensated cirrhosis • Coronary artery disease, heart failure, serious dysrythmia • Proliferative diabetic retinopathy • Kidney transplant patients • Renal impairment (ribavirin)

  19. 2011: Telaprevir and Boceprevir for HCV Genotype 1

  20. Sustained Virologic Response: Telaprevir plus Peg Interferon Plus Ribavirin PR 74–79* PR48 166/361 T12/PR 683/903 n/N = *p<0.0001 T12/PR vs PR48 (79% versus 46%) in ADVANCESVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used INCIVO (telaprevir) EU SmPC

  21. SVR rates with boceprevir plus PR versus PR alone * * PR48 137/363 BOC RGT 233/368 BOC44/PR48 242/366 n/N = *p<0.001 for both boceprevir arms versus PR48 SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24. If there was no such value, the follow-up Week value was carried forward VICTRELIS (boceprevir) EU SmPC

  22. Adverse Events with Telapravir and Bocepravir

  23. Important Safety Information Contraindicated Drugs and Other Precautions for Telaprevir *These interactions have been studied; †Impaired renal/hepatic function; ‡No clinical data are available regarding the treatment of organ transplant patients with TRADENAME in combination with peg-IFN/RBV. Therefore, the use of TRADENAME in organ transplant patients is not recommended; §Normal renal/hepatic function.

  24. December 2013Simeprevir and Sofosbuvir

  25. Efficacy With Simeprevir + P/R in Tx-Naive GT1 Patients: Phase III Trials • SMV + P/R for 12 wks followed by 12-36 wks of P/R (placebo control) Simeprevir + P/R Placebo + P/R 100 100 82 85 84 80 80 80 58 58 53 60 60 53 52 50 43 SVR (%) 40 40 29 20 20 419/521 133/264 138/165 36/83 49/84 23/44 228/267 70/133 188/229 60/113 18/31 5/17 n/N = n/N = 0 0 Overall GT1aWithoutQ80K GT1a WithQ80K GT1b No Cirrhosis Cirrhosis Jacobson I, et al. EASL 2013. Abstract 1425.

  26. Simeprevir Is Well Tolerated Bilirubin Hemoglobin 200 30 180 20 SMV + P/RP/R SMV + P/RP/R 160 Mean (µmol/L) Mean (µmol/L) 140 10 120 100 0 0 2 4 8 12 16 20 24 36 48 0 2 4 8 12 16 20 24 36 48 Wks Wks • Mild unconjugatedhyperbilirubinemia→ transporter • No anemia signal beyond P/R • Rash up to 25% (mild) Manns M, et al. EASL 2013. Abstract 1413.

  27. Efficacy With Sofosbuvir + P/R in Tx-Naive GT1/4/5/6 Patients: Phase III Trials • Single-arm study of sofosbuvir + P/R for 12 wks SVR12 According to GT SVR12 According to Fibrosis Level 100 96 100 100 92 89 80 80 80 60 60 SVR12 (%) SVR12 (%) 40 40 20 20 n/N = 261/292 27/28 7/7 252/273 43/54 0 0 GT1 GT4 GT5/6 No Cirrhosis Cirrhosis Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

  28. Efficacy of Sofosbuvir in GT2 Treatment Naive[1] Treatment Experienced[2] 12 wks of SOF + RBV PegIFN/RBV 16 wks of SOF + RBV 100 98 96 100 100 91 82 78 80 80 62 60 60 60 SVR12 (%) 40 40 20 20 n/N = 25/26 23/23 6/10 7/9 n/N = 58/59 44/54 10/11 8/13 0 0 No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis 1. Gane E, et al. EASL 2013. Abstract 5.2. Jacobson I, et al. N Engl J Med. 2013;368:1867-1877. GT2

  29. FDA Approved Indications for Sofosbuvir

  30. DO NOT USE TELAPREVIR OR BOCEPREVIR

  31. The FutureInterferon Free Regimens

  32. IFN-Free Therapy for Tx-Naive GT1 HCV C-WORTHY12-wk regimens[4] AVIATOR[1] ABT-450/RTV + ABT-333 + ABT-267 + RBV LONESTAR[2] AI443-014[3] Daclatasvir + Asunaprevir + BMS-791325for 12 wks SOF/LDV FDC 8 wks MK-5172 + MK-8742 20 mg + RBV SOF/LDV + RBV 8 wks MK-5172 + MK-8742 50 mg + RBV 24 wks SOF/LDV FDC 12 wks 12 wks MK-5172 + MK-8742 50 mg 100 100 95 95 100 96 96 100 100 100 92 90 89 80 80 80 80 60 60 60 60 SVR12/24 (%) 40 40 40 40 20 20 20 20 n = 77 21 19 20 80 27 13 79 25 0 0 0 0 1. Kowdley K, et al. EASL 2013. Abstract 3. 2. Lawitz E, et al. AASLD 2013. Abstract 215. 3. Everson GT, et al. AASLD 2013. Abstract LB-1. 4. Lawitz E, et al. AASLD 2013. Abstract 76.

  33. Is the demise of Hepatology imminent ? • HCV cure rate approaching 95% • HBV incidence declining rapidly due to vaccination • Treatment of HBV and HCV using direct acting antivirals is safe, simple and can be handled by internists. • Alcoholic liver disease and NASH can be handled by internists • Only end stage liver disease and liver transplant patients need specialty care ?

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